Interx Research Corporation

Yu-Neng Kuo

Nicolae S Bodor

Takeru Higuchi

Kenneth B Sloan

There is provided exceptionally stable and useful pro-drug forms of theophylline having the formula: ##STR1## wherein R represents a straight or branched phenylalkenyl group having 2-8 carbon atoms in the alkenyl portion. The compounds of this invention are useful in the treatment of asthma in warm-blooded animals. Upon administration, the compounds of this invention slowly go into solution and subsequently cleave prior to and/or during the absorption process, releasing theophylline in a sustained manner at a non-toxic, therapeutic level; that is, without the large blood level variations normally observed when theophylline per se is administered.

Stable pro-drug forms of theophylline

There is provided novel and useful pro-drug forms of theophylline having the formula: ##STR1## wherein R represents a member selected from the group consisting of a straight or branched C.sub.4 -C.sub.20 alkyl group, a straight or branched C.sub.14 -C.sub.20 alkenyl group, a substituted phenyl group or a substituted or unsubstituted naphthyl group whose substituents are selected from the group consisting of a hydroxy group, a C.sub.1 -C.sub.4 alkyl group, a C.sub.1 -C.sub.4 alkoxy group, a C.sub.1 -C.sub.14 acyloxy group, and a halogen atom (Cl, Br, I), and a substituted or unsubstituted heteroaromatic group whose substituents are selected from the group consisting of a hydroxy group, a C.sub.1 -C.sub.4 alkyl group, a C.sub.1 -C.sub.4 alkoxy group, a C.sub.1 -C.sub.4 acyloxy group, and a halogen atom (Cl, Br, I), and wherein A presents a member selected from the group consistng of a --CO-- group, a --CO--(CH.sub.2).sub.n --C-- group, wherein n represents an integer of from 1 to 16, a --CO--CH=CH--CO-- group (cis or trans), ##STR2## AND A ##STR3## group. The compounds of this invention are useful in the treatment of asthma in warm-blooded animals. Upon administration, the compounds of this invention slowly go into solution and subsequently cleave prior to and/or during the absorption process, releasing theophylline in a sustained manner at a non-toxic, therapeutic level; that is, without the large blood level variations normally observed when theophylline per se is administered.

Useful pro-drug forms of theophylline

There is provided, a method for synthesizing certain selected pro-drug forms of theophylline, having the formula: ##STR1## wherein R represents a member selected from the group consisting of a straight or branched C.sub.4 -C.sub.20 alkyl group, a straight or branched C.sub.4 -C.sub.20 alkenyl group, a substituted phenyl group or a substituted or unsubstituted naphthyl group whose substituents are selected from the group consisting of a hydroxy group, a C.sub.1 -C.sub.4 alkyl group, a C.sub.1 -C.sub.4 alkoxy group, a C.sub.1 -C.sub.4 acyloxy group, and a halogen atom and a substituted or unsubstituted heteroaromatic group whose substituents are selected from the group consisting of a hydroxy group, a C.sub.1 -C.sub.4 alkyl group, a C.sub.1 -C.sub.4 alkoxy group, a C.sub.1 -C.sub.4 acyloxy group, and a halogen atom, and wherein A represents a member selected from the group consisting of a --CO-- group, a --CO--(CH.sub.2).sub.n --CO-- group, wherein n represents an integer of from 1 to 16, a --CO--CH=CH--CO-- group (cis or trans) a ##STR2## group and a ##STR3## group, which comprises: Reacting theophylline with an appropriate acid in the presence of dimethylformamide, COCl.sub.2 or SOCl.sub.2, organic tertiary or aromatic amine base or inert carrier gas for removing HCl, and suitable solvent. The compounds prepared by this process are useful for treating asthma by releasing theophylline in sustained manner.

Method for synthesizing certain selected pro-drug forms of theophylline

There is provided novel and useful pro-drug forms of theophylline having the formula: ##SPC1## Wherein R represents a member selected from the group consisting of a straight or branched C.sub.4 -C.sub.20 alkyl group, a straight or branched C.sub.4 -C.sub.20 alkenyl group, a substituted phenyl group of a substituted or unsubstituted naphthyl group whose substituents are selected from the group consisting of a hydroxy group, a C.sub.1 -C.sub.4 alkyl group, a C.sub.1 -C.sub.4 alkoxy group, a C.sub.1 -C.sub.4 acyloxy group, and a halogen atom (Cl, Br, I), and a substituted or unsubstituted heteroaromatic group whose substituents are selected from the group consisting of a hydroxy group, a C.sub.1 -C.sub.4 alkyl group, a C.sub.1 -C.sub.4 alkoxy group, a C.sub.1 -C.sub.4 acyloxy group, and a halogen atom (Cl, Br, I), and wherein A represents a member selected from the group consisting of a --CO-- group, a --CO--(CH.sub.2).sub.n --CO-- group, wherein n represents an integer of from 1 to 16, a --CO--CH=CH--CO-- group (cis or trans), a ##SPC2## Group, and a ##SPC3## Group. The compounds of this invention are useful in the treatment of asthma in warm-blooded animals. Upon administration, the compounds of this invention slowly go into solution and subsequently cleave prior to and/or during the absorption process, releasing theophylline in a sustained manner at a non-toxic, therapeutic level; that is, without the large blood level variations normally observed when theophylline per se is administered.

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Lawrence, KS, United States of America

Yu-Neng Kuo